Is posttransplant lymphoproliferative disorder (PTLD) caused by any specific immunosuppressive drug or by the transplantation per se?

BACKGROUND: An association between posttransplant lymphoproliferative disorder (PTLD) and cyclosporine A (CsA) and OKT3 has often been postulated on the basis of retrospective studies, although a randomized study with PTLD as the endpoint will probably never be performed. Because focus on PTLD coincided with the use of these drugs, a bias could be suspected. METHODS: In a retrospective, nonrandomized study, we reevaluated all lymphoma-like lesions arising in kidney-transplant patients grafted at our center during 1969 to 1998 and observed up to 2002. Case pathology was reviewed, and an association with Epstein-Barr virus (EBV) infection (and latency pattern) was assessed. RESULTS: We did not find any significant difference in the incidence of PTLDs when comparing the prednisolone/azathioprine, and CsA eras (P=0.89), the periods before or after OKT3 (P=0.61), and those before or after antilymphocyte globulin (ALG) (P=0.22). Occurrence time was shorter in the CsA (P=0.059), OKT3 (P=0.007), and ALG (P=0.007) eras. In the OKT3 era, 182 patients received, and 224 did not receive, OKT3; after the same observation time, there had been eight and five PTLDs, respectively (P=0.34). The use of mycophenolate mofetil (MMF) was associated with a reduction in the number of PTLDs (P=0.01). EBV was detected in 16 of 21 (76%) cases. CONCLUSIONS: We found no evidence to implicate any one drug regime preferentially in the development of PTLDs. The risk of developing PTLD seems to be a result of the whole transplantation process, which includes the antigenicity of the foreign graft, the immunosuppression resulting in inadequate cytotoxic T-cell activity, and the result of EBV infection. An important minority of cases are EBV negative.

Long-term follow-up of kidney transplant patients with posttransplant lymphoproliferative disorder: duration of posttransplant lymphoproliferative disorder-induced operational graft tolerance, interleukin-18 course, and results of retransplantation.

BACKGROUND: Posttransplant lymphoproliferative disorder (PTLD) can be resolved in many transplant patients by the reduction or cessation of immunosuppression, after which many grafts continue to function as the result of a form of operational tolerance. When graft function deteriorates, retransplantation may be an option. Cytokines such as interleukin (IL)-10 and IL-18 may play a role in PTLD tolerance induction and tumor regression. We report long-term follow-up on the duration of graft tolerance and the course of retransplantation in a series of patients who underwent kidney transplantation and demonstrated PTLD, and in whom we were able to perform IL-18 analyses. RESULTS: Patients were followed for up to 7 years after PTLD diagnosis. Treatment consisted of immunosuppression cessation with radiation therapy in cases with overt monomorphic lymphomas. All patients' PTLDs were resolved, and all patients but one (whose graft was removed) demonstrated a period of operational graft tolerance of up to 5 years. Five patients underwent retransplantation without sign of recurrence of the PTLD up to 3 years after transplantation. In the eight patients analyzed, IL-18 increased significantly during PTLD regression and follow-up in those with long-term operational tolerance. CONCLUSION: We report on a series of patients with resolved PTLDs demonstrating long-term recurrence-free survival, of whom most experienced a long period of operational graft tolerance. IL-18 seems to play a role in the resolution of the PTLDs. Five patients underwent retransplantation with standard immunosuppression without recurrence. A previous diagnosis of PTLD should not be regarded as a contraindication for later retransplantation.

Steroid-free immunosuppression in renal transplantation: a long-term follow-up of 100 consecutive patients.

BACKGROUND: Our goal in clinical renal transplantation is to establish a steroid-free immunosuppressive protocol that not only promotes long-term patient and graft survival, but also improves the overall well-being of the patients. METHODS: In a prospective, nonrandomized, clinical study 100 consecutive patients transplanted with first and second grafts were discharged from our center with functioning grafts 1996-1999 and followed for up to 4 1/2 years. Patients received steroid-free immunosuppression with an initial 10-day antithymocyte (ATG) induction and maintenance therapy with cyclosporine (CsA) and mycophenolate mofetil (MMF). No steroids were given. RESULTS: After an observation time of up to 4 1/2 years, 1-, 2-, 3-, and 4-year graft survivals of 97, 96, 90, and 82% were observed, with no correlation to HLA-matching, kidney disease, donor age or type, or number of transplants. Ninety-nine patients (1 died or peritonitis after returning to dialysis) were alive and well. Ninety grafts were functioning well, 9 patients returned to dialysis due to recurrence of hemolytic uremic syndrome, and glomerulonephritis in 2 and chronic rejection in 7 grafts after 7-36 months (3 due to non-compliance after 7-30 months). All 7 children below the age of 15 are alive, with well-functioning grafts, except 1 with recurrence of glomerulonephritis who returned to dialysis after 2 1/2 years. There were 13 acute rejections (13%), 10 early (first 3 months) (10%), and 3 late (6-42 months) (3%). All acute rejection episodes were successfully reversed. No lymphomas were observed. CONCLUSIONS: Our first-line, steroid-free immunosuppressive protocol allows initial graft function, provides a safe level of long-term graft survival and function with a very low rejection rate, gives an acceptable rate of side effects, and possesses the potential for lowering the incidence of chronic rejection over the long-term. Compared with protocols that discontinue steroids after the initial posttransplant period, a steroid-free protocol avoids the increased risk of infection, body disfigurement, and other steroid-induced side-effects in the early posttransplant period. It also avoids the long-term risks of steroid use and the increased risk of rejection when the steriods are withdrawn.

Cancer risk in patients on dialysis and after renal transplantation.

The increased risk of cancer in patients who have had kidney transplants has mainly been attributed to immunosuppressive therapy; however, the prior period of uraemia and dialysis has also been postulated as a cofactor. We analysed cancer risk retrospectively in a cohort of 4178 patients undergoing renal replacement therapy, of whom 3592 were treated with dialysis alone and 1821 later had transplants. We found that excess cancer risk in such patients occurred after transplantation and not during dialysis.

Preventing acute rejection, Epstein-Barr virus infection, and posttransplant lymphoproliferative disorders after kidney transplantation: use of aciclovir and mycophenolate mofetil in a steroid-free immunosuppressive protocol.

BACKGROUND: A widely held view is that any increase in the potency of an immunosuppressive agent will lead to an increase in infection and malignancy, such as life-threatening Epstein-Barr virus (EBV) induced posttransplant lymphoproliferative disorders (PTLD). We tested this paradigm by studying the effect of adding mofetil to a steroid-free protocol under cover of high-dose aciclovir prophylaxis on the number of acute rejections, EBV infections and PTLDs after kidney transplantation. METHODS: EBV serology was performed in 267 consecutive renal transplantations (1990-1997). All were treated with cyclosporine with an initial 10-day antilymphocyte globulin course, supplemented from September 1995 with MMF. In 208 consecutive transplantations after June 1992 aciclovir 3200 mg/day was given for 3 months posttransplantation. RESULTS: After an observation period of up to 7 years we found that: (1) primary or reactivated EBV infection (PREBV) was correlated to acute rejection (treated with OKT3; P<0.00005) and to the incidence of PTLD (P=0.03; P=0.01, if Hodgkin's disease is included); (2) aciclovir protected against PREBV (P<0.00005) and (3) adding mofetil to the immunosuppressive protocol reduced PREBV further (P=0.0001), (4) in 78 transplantations treated with cyclosporine/antilymphocyte globulin/mofetil we observed only 10 acute rejections (P=0.0001), 10 PREBVs (P<0.00005), and no PTLDs compared with the cyclosporine/antilymphocyte globulin group (P=0.04). CONCLUSIONS: Supplemental immunosuppression with mofetil protects against acute rejection. In combination with aciclovir, there is also a reduction in the number of PREBVs, apparently as a result of both direct viral prophylaxis and better rejection control, and in the incidence of EBV-induced PTLD.

Interleukin-10 and posttransplant lymphoproliferative disorder after kidney transplantation.

BACKGROUND: Posttransplant lymphoproliferative disorder (PTLD) is a life-threatening complication of transplantation, which comprises a morphologically and clinically heterogeneous spectrum of B-lymphocyte diseases. Risk factors include primary or reactivated Epstein-Barr virus (EBV) infection, and the type and duration of immunosuppression. Interleukin-10 (IL-10) is a pleiotropic cytokine, produced primarily by T-helper 2 (Th2) lymphocytes in the later stages of T-cell activation, suggested to play a role in EBV-associated PTLD. We recently reported preliminary findings on IL-10 in relation to the development of PTLD in three kidney transplanted patients. The study now includes nine patients that could be followed before and/or after the occurrence of lymphoma. METHODS: Nine patients with lymphomas (eight PTLDs and one Hodgkin's disease) were diagnosed among 268 consecutive renal transplantations (1990-1997). All were treated with cyclosporine with an initial 10-day course of antilymphocyte globulin, supplemented from 1995 with mycophenolate mofetil. Serum antibodies against EBV were detected using recombinant antigens. A double sandwich enzyme-linked immunosorbent assay using rabbit antibodies to purified human recombinant IL-10 was employed; the assay is specific for human natural and viral IL-10. RESULTS: Three patients experienced primary EBV infection, five reactivated EBV infections, and one did not change EBV status. Three patients had a fulminant course and died with EBV-associated PTLD confirmed post mortem. The other six are alive and are apparently cured. Treatment was immediate discontinuation of immunosuppression (in all PTLDs) and long-term high-dose aciclovir in all but one. Two patients have maintained excellent graft function for 3 and 2 years, respectively, without immunosuppression and are now in a state of operational tolerance. In three of four cases with initial lymphoma, EBV infection (primary or reactivation) preceded the increase in IL-10. In all four cases, the IL-10 increase preceded the PTLD diagnosis. In six cases, IL-10 could be followed after treatment showing either immediate zero or a decrease to zero. CONCLUSION: IL-10 seems to play a role in EBV-associated PTLD. Moreover, IL-10 may have an important role in transplant tolerance by inducing long-lasting anergy to donor- and host-specific alloantigens, perhaps caused by down-regulation of Th1 cytokines in the graft. If substantiated, this may provide new insight into the pathogenesis of PTLD introducing new strategies for prevention and therapy of PTLD, and for the induction of tolerance in transplanted patients.

[The history of transplantation]. / Transplantationens historie.

Transplantation is a young discipline with a long history, of which this paper therefore only describes fragments. The story is created by the pioneers, who made the basis for transplantation. I have focused on those who received the Nobel prize for their work, Carrel (1912), Burnet, Medawar (1960), Snell, Dausset, Benacerraf (1980), Elion, Hitchings (1988), and Thomas and Murray (1990), however many others deserve to be mentioned. Parallelled with the development of transplantation, other disciplines like immunology have grown up. Today we can transplant kidneys, hearts, livers, and bone marrow as a kind of routine. However we do treat on the brink of medicine, and the suppression of the immune apparatus has a prize, which is a tendency to atherosclerosis, virus infections and malignancies.

Lessons from transplantation and future perspectives.

Organ transplantation is now a routine treatment for a number of chronic kidney, heart, lung, and liver diseases. We have accumulated much knowledge about these treatments in the respective disciplines, and it seems appropriate to reflect on some general "across-the-border" lessons that may be important for medicine as a whole. The natural history of several diseases has been extended; however, we have also learned much about temporary organ replacement, with the possibility of treating and, perhaps, also preventing some diseases in ways that were not possible in the past. This study explores the phenomenon of temporary organ replacement, whereby organs that are in danger in losing their function may recover in quiescence. It raises the question of whether there might be a common, underlying mechanism-such as apoptosis-for some very different diseases. Pharmacological interventions designed to modulate apoptosis are being developed that will hopefully reduce the amount of time needed for organs to recover their function. We have learned some lessons, but are there more possibilities that need to be explored?

Steroid-free immunosuppression after kidney transplantation with antithymocyte globulin induction and cyclosporine and mycophenolate mofetil maintenance therapy.

BACKGROUND: Our goal in clinical renal transplantation is to find immunosuppressive procedures that not only promote long-term patient and graft survival but also improve the overall well-being of the patients. METHODS: In a retrospective consecutive clinical study with historical controls, 68 patients were discharged from our center with functioning grafts between September 1995 and December 1997. Patients received steroid-free immunosuppression using an initial 10-day antithymocyte globulin induction and maintenance therapy with cyclosporine and mycophenolate mofetil (MMF). No steroids were given. RESULTS: After an observation for up to 2.5 years (median 488 days, range 127 to 945 days), 66 patients (one died from sepsis after 6 months, and one died of peritonitis after returning to dialysis) were alive and well. Sixty-four grafts were functioning well, hemolytic uremic syndrome recurred in one graft, one graft had to be removed for noncompliance, and two patients returned to dialysis after chronic rejection-one after 8 months (the patient who died in peritoneal dialysis) and one (a third graft in an antibody-positive patient) 16 months after transplantation. We observed only 10 acute rejections (15%), a rate significantly lower (P=0.0006) than the 71 acute rejections observed in 190 previous consecutive transplants (37.4%) treated without MMF but otherwise after exactly the same protocol. In further comparison, the MMF-treated group also showed an equivalent (P=NS) rate of cytomegalovirus infections and a lower rate (P<0.00005) of Epstein-Barr virus infections. Graft function was excellent (median serum creatinine below 200 micromol/L at 1 year), and no malignancies were observed in the MMF-treated patients. Side effects were mainly leukopenia and two gastrointestinal disturbances. CONCLUSIONS: Our first-line, steroid-free immunosuppressive protocol allows initial graft function, provides a safe level of long-term graft survival and function with a very low rejection rate, gives an acceptable rate of side effects, and possesses the potential for lowering the incidence of chronic rejection over the long-term. Compared with protocols that discontinue steroids after the initial posttransplant period, a steroid-free protocol avoids the increased risk of infection and body disfigurement in the early posttransplant period. It also avoids the long-term risks of steroid use and the increased risks of rejection when the steroids are withdrawn.

Prophylaxis against herpes infections in kidney transplant patients with special emphasis on CMV.

METHOD: Since 1990, we have treated all kidney transplanted patients with cyclosporin (CsA)+ an initial 10 d antilymphocyte globulin (ALG) course, from September 1995 supplemented with mycophenolate mofetil (MMF). In 170 consecutive transplantations from June 1992 to the end of 1996, aciclovir 3200 mg/d (adjusted for kidney function and in children to age) was given prophylactically for 3 months post-transplantation (Tx), monitored with systematic and frequent tests for HSV and CMV. In case of CMV infection, we gave ganciclovir intravenously (oral ganciclovir from 1996) in doses according to kidney function for 3 months, followed by a further 3 months observation and monitoring period. In case of acute cellular rejection, ganciclovir was given during the 10-d OKT3 course and 1 week further. In case of delayed graft function combined with aciclovir side effects, ganciclovir was given until aciclovir could be reintroduced. RESULTS: 39% were HSV seronegative at Tx. There were no seroconversions or reactivations within the observation period. No mucocutaneous HSV infections was observed. No resistant strains developed. 26% were both HSV and CMV negative at Tx. 52% were CMV negative at Tx. 30% experienced a CMV infection post-transplant. The patients were grouped according to CMV status in the donor (D) and recipient (R) before Tx. We found approximately the same number of patients in the 4 CMV groups D-/R-, D+/R-, D-/R+ and D+/R+. Most infections occurred in the D+/R- group compared to D-/R- (p = 0.009). A significant increase in the number of CMV infections occurred in this subgroup when we gave reduced doses in case of delayed graft function (p = 0.015), from 1994. We observed only 1 CMV disease (in 1992). Serological EBV testing were performed concomitantly. No correlation was seen between CMV and EBV infections. From September 1995 we have treated all transplanted patients (n = 40) with CsA/ALG/MMF. We found no significant increase in CMV infections in this group. CONCLUSIONS: Prophylaxis with aciclovir (combined with ganciclovir during acute rejections and in case of delayed graft function with aciclovir side effects) gives a good protection against HSV and CMV infections and prevents CMV disease effectively. High-dose aciclovir post-transplantation (or shift to ganciclovir) seems to be important to obtain effective prophylaxis. Better immunosuppression with MMF does not result in more CMV infections.

Indications of immunological tolerance in kidney transplantation.

As a complication to immunosuppressive treatment in allotransplantation, malignant diseases such as post-transplant lymphoproliferative disorder (PTLD) may occur. The patient in the present case is a 21-year-old man transplanted at the age of 11 with a kidney from his mother and at the age of 15 with a kidney from his father. During the immunosuppressive treatment the patient developed PTLD resulting in the withdrawal of the immunosuppressive drugs. At the time of writing, the immunosuppressive drugs have been withdrawn for more than 3 years. We report the findings of a state of donor-specific tolerance occurring after transplantation. Post-transplant cells from the patient show a non-reactive response in mixed lymphocyte cultures (MLCs) to cells from both the mother and the father. We demonstrate a reduction in the mRNA expression of the Thl cytokines IL-2 and IFN-gamma in the very same MLCs. The expression of Th1 cytokine mRNA was measured semi-quantitatively using competitive reverse transcription-polymerase chain reaction (RT-PCR). The reduction in the Th1 cytokine mRNA expression is not seen in the MLCs with patient cells against cells from a paternal HLA-A, B and DR-matched individual, suggesting the influence of other allorecognition factors than HLA-A, B and DR. Detection in vitro of a lowered expression of Th1 cytokine mRNA supports the notion of these mRNAs as indicators of post-transplant tolerance. Further studies will reveal whether the cytokine mRNA measurements on short time stimulated lymphocytes can be used more generally as a monitoring parameter of tolerance in kidney transplantation.

Pediatric renal transplantation without steroids.

Pediatric renal transplant patients present a number of challenges and problems, especially the inhibited post-transplant growth seen in children receiving standard immunosuppressive triple therapy that includes steroids. We report the successful use of steroid-free immunosuppression since 1990 in 14 pediatric renal allograft recipients who received a 10-day initial course of anti-lymphocyte globulin and surface area-adjusted doses of cyclosporine, 7 of whom also received mycophenolate mofetil (MMF) as maintenance immunosuppression. Only 1 patient died (3 months after transplantation as a result of a primary Epstein-Barr virus infection-induced lymphoproliferative disorder), 1 patient's graft never functioned, and another patient lost his graft after 3 years because of chronic rejection. Three patients experienced early acute cellular rejection, which resolved in 2 cases with OKT3, and in the 3rd with MMF. There were no late acute rejections. All patients evidenced growth and a growth spurt under this regimen. We conclude that all the pediatric patients benefited from our steroid-free protocol and that this protocol is superior to conventional triple therapies, which entail the eventual reduction and discontinuation of steroids, a procedure that not only inhibits growth but also carries an additional risk of acute rejection due to a steroid-adapted immune response.

De novo cancers complicating renal transplantation: experience in the Nordic countries.

OBJECTIVES: This report summarizes the experience in the Nordic countries with de novo cancer complicating renal transplantation and the prospects of a new Nordic EU-SPONSORED study (EURO-CAT) covering all kinds of organ transplantations. METHODS: Epidemiological studies are performed using standard methods of cohort analysis. The expected numbers of cancer cases in each stratum are calculated by applying the stratum- and site-specific cancer incidence rate of the national population to the appropriate number of person-years at risk. The observed/expected ratio is taken as the relative risk (standardized incidence ratio, SIR). Differences in SIRs between subcohorts are tested by evaluating the rate ratio. Laboratory methods include immunopathological, virus serological cytokine and tissue type analyses. Treatment includes discontinuation of immunosuppression and long-term high dose aciclovir. RESULTS: In our most recent analyses an incidence 3-5 times higher than that of the general population has been found, including most types of tumors, however with an uneven pattern with emphasis on lip-cervical-, vulvar-, urological-, skin cancers and lymphoprolipherative disorders (PTLD). Most tumors occur early (incl. PTLD) after transplantation, tumors of the skin however later and with an increase with time. In our present analysis we follow all types of organ transplantation, up to the most recent date, to consider the many new immunosuppressive agents for their risk of inducing cancer. Laboratory analyses have pointed to IL-10 as a possible cofactor in the development of EBV-induced PTLD. Treatment with aciclovir and discontinuation of immunosuppression may in some cases lead to recovery from the malignancy, sometimes even without harming the graft function.

Development of anti-OKT3 antibodies after OKT3 treatment.

The development of IgG and IgM anti-OKT3 antibodies the first 90 days after start of OKT3 treatment for acute cellular rejection was determined by ELISA in 25 consecutive renal transplant patients. The ELISA positive sera were then tested for neutralizing OKT3 antibodies by immunofluorescence inhibition assay utilizing the FACScan. The number of IgM positive patients was highest, four (16%) after 10 days of treatment and then declined. The highest number of patients, thirteen (56%) with IgG antibodies was found after 60 days. Sera with only IgM antibodies or with low IgG titers (< 1:100) did not neutralize OKT3. Five patients (20%) developed neutralizing antibodies. All of these patients had received OKT3 during an earlier transplantation. In four of these patients, the ACR had been reversed successfully before the development of antibodies, and in the last patient the ACR was reversed by a second course of Minnesota-ALG and increasing the dose of Cyclosporine. Monitoring the development of neutralizing anti-OKT3 antibodies is valuable in patients who have previously received OKT3 treatment.